Tuberculosis (TB) is a major public health concern in Brazil. This ICIDR proposal builds on a pre-existing collaboration between Drs. Ellner, Dietze, Rodrigues and Palaci and will enhance the scientific infrastructure and training capabilities of the Nucleo de Doengas Infecciosas (NDI) in Vitoria Brazil and provide information essential to address the TB problem. Our hypothesis is that strain variation in Mycobacterium tuberculosis (MTB) is a determinant of the extent of transmission of infection in household contacts with pulmonary TB, the risk of progressing from infection to disease, and the protection conferred by prior mycobacterial infection/vaccination. Our group has discovered a set of synonymous single nucleotide polymorphism (SNP) markers in MTB and used them to construct an unequivocal evolutionary tree of the species making it possible to precisely determine how different clinical strains are related, and to identify strain families likely to share phenotypic traits. We also have discovered new mechanisms for genomic diversity among clinical MTB strains. Overall, these discoveries have uncovered a hitherto unsuspected degree of polymorphism in MTB that may allow it to adapt to host immune responses by antigenic variation and changes in its other cellular functions. A novel household contact design conducted in Vitoria, Brazil will be used to accomplish the following: Aim 1. To determine whether some clinical strains are more transmissible or cause more disease progression in infected patients, whereas other strains have the opposite phenotype, and to determine whether strains with different phenotypes diverge in the way they interact with the host immune system. Aim 2. To determine if strains vary in the way that they interact with the innate immune system and the degree to which host differences influence this interaction. Aim 3. To determine the degree to which adaptive immunity to MTB is strain-specific, and to discover the principal strains or bacterial factors that could be combined in a future vaccine effective against all MTB strains. This program creates a collaboration among leading epidemiologists, immunologists, molecular biologists and microbiologists from the U.S. and Brazil that will enable cutting edge research and training on crucial aspects of tuberculosis biology and immunology in human populations using an innovative epidemiological study design.